Paternal methamphetamine exposure differentially affects first and second generations in mice

Amphetamine-type stimulants are abused worldwide, and methamphetamine (METH) accounts for a large majority of seized abused drug cases. Recently, the paternal origin of health and disease theory has been proposed as a concept wherein paternal factors influence descendants. Although METH abuse is more common among males, its effects on their descendants were not examined. Therefore, we investigated the effects of paternal METH exposure on F1 and F2 levels in a mouse model. Sires were administered METH for 21 days and mated with female mice to obtain F1 mice. Growth evaluations (number of births, survival rate, body weight, righting reflex, cliff avoidance tests, and wire-hanging maneuver) were performed on F1 mice. Upon reaching six weeks of age, the mice were subjected to spontaneous locomotion, elevated plus-maze, acute METH treatment, and passive avoidance tests. Additionally, RNA-seq was performed on the striatum of male mice. Male F1 mice were mated with female mice to obtain F2 mice. They were subjected to the same tests as the F1 mice. Paternal METH exposure resulted in delayed growth and decreased memory function in F1 mice, overweight in F2 mice, decreased METH sensitivity, and reduced anxiety-related behaviors in female F2 mice. Enrichment analysis revealed significant enrichment of terms related to behavior in F1 and protein folding in F2. These results indicated that the effects of paternal METH exposure vary across generations. The effects of paternal factors need to be examined not only in F1, but also in F2 and beyond.